Project Summary/Abstract: Two million broken bones accounting for $19 billion dollars in medical costs occur each year because of the ?silent disease? of osteoporosis, which often progresses with no noticeable symptoms prior to fracture, and is difficult to diagnose with respect to future fracture risk. Interestingly, the best predictor of future fracture risk is a previous history of fracture at any skeletal site, even after controlling for bone mineral density. The etiology of this relationship is unknown, but it is likely that fracture causes a systemic bone resorption response that under certain conditions can actively and permanently compromise the entire skeleton. However, systemic bone loss following fracture has not been thoroughly characterized, and the specific mechanisms of this bone loss have not been identified. Preliminary data from our lab show that bone fracture actively decreases trabecular bone volume at distant skeletal sites within two weeks post-injury in mice. However, significant knowledge gaps remain concerning factors that affect the loss and recovery of bone following fracture, and identification of mechanisms contributing to this adaptive response. Identification of these factors is a crucial step toward identifying therapeutic targets and the window of opportunity for treatment. In the proposed studies we will determine age- and sex-based differences, dose-dependence (based on injury severity), and specific mechanisms of systemic bone loss following fracture in mice, including injury-induced inflammation and osteocytic perilacunar remodeling. We hypothesize that: 1) male and female mice will exhibit different magnitudes of systemic bone loss following fracture, 2) recovery from this bone loss will be diminished in older mice, 3) the magnitude of systemic bone loss will be predicted by the severity of injury, 4) inhibition of the inflammatory cytokine interleukin 6 (IL-6) will reduce the systemic bone loss response, and 5) osteocyte- deficient mice will exhibit a reduced bone resorption response. In Aim 1 we will determine age- and sex-based differences in systemic bone loss and recovery following femur fracture in mice. In Aim 2 we will determine the dose-dependence of systemic bone loss based on injury severity, and the contribution of injury-induced inflammation, in particular IL-6. In Aim 3 we will determine the contribution of osteocytes to the systemic bone loss response using a genetic mouse model of osteocyte dysfunction (Bcl-2 transgenic mice). These studies will investigate the novel hypothesis that bone fracture actively decreases bone mass systemically, thereby increasing the risk of future fractures at all skeletal sites. These studies will expand our understanding of the systemic effects of an acute injury, and may lead to therapeutic strategies aimed at preserving the long-term skeletal health of osteoporotic patients.